During long-term endurance exercise after liver glycogen is depleted, hepatic synthesis of glucose from lactate and other precursors becomes the only means for maintenance of blood glucose. Muscle glycogenolysis and lactate production becomes essential for providing substrate for adequate glucose production by the liver. These proposed studies will focus on hormonal and metabolic mechanisms for muscle production of lactate in excess of endogenous energy requirements during exercise. That is, what are the signals which stimulate glycogenolysis in excess of muscle requirements for pyruvate oxidation? What signals insure that glycolytic intermediates resulting from accelerated glycogenolysis will be diverted into the lactate pathway instead of into the oxidation pathway when gluconeogenesis is required for maintenance of blood glucose? To elucidate possible control mechanisms responses of muscle cAMP, fructose 2,6- bisphosphate, glucose 1,6-bisphosphate, and malonyl CoA will be correlated with plasma epinephrine and insulin and with rates of glycogenolysis in fed and fasted rats exercising on the treadmill for prolonged periods at different work rates. To elucidate which changes are controlled by plasma epinephrine, responses of saline- infused adrenodemedullated rats will be compared with sham operated rats and with adrenodemedullated given replacement infusions of epinephrine during exercise. Responses of glucose- infused and of endurance trained rats will be investigated. Using the rat hindlimb perfusion procedure, the effects of epinephrine and insulin on the above putative signal molecules will be investigated in muscle with respect to actual rate of lactate production. These studies will provide new basic information on the roles of epinephrine and insulin in controlling this aspect of glucose production during exercise.